CA2357037A1 - Optical sorting method - Google Patents

Optical sorting method Download PDF

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Publication number
CA2357037A1
CA2357037A1 CA002357037A CA2357037A CA2357037A1 CA 2357037 A1 CA2357037 A1 CA 2357037A1 CA 002357037 A CA002357037 A CA 002357037A CA 2357037 A CA2357037 A CA 2357037A CA 2357037 A1 CA2357037 A1 CA 2357037A1
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Canada
Prior art keywords
optical properties
gene product
genetic
genetic element
genetic elements
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Granted
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CA002357037A
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French (fr)
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CA2357037C (en
Inventor
Andrew Griffiths
Dan Tawfik
Armin Sepp
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United Kingdom Research and Innovation
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Individual
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Priority to CA002584933A priority Critical patent/CA2584933A1/en
Priority to CA002479551A priority patent/CA2479551A1/en
Publication of CA2357037A1 publication Critical patent/CA2357037A1/en
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Publication of CA2357037C publication Critical patent/CA2357037C/en
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C12N15/1075—Isolating an individual clone by screening libraries by coupling phenotype to genotype, not provided for in other groups of this subclass
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C12N15/1062—Isolating an individual clone by screening libraries mRNA-Display, e.g. polypeptide and encoding template are connected covalently
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6811—Selection methods for production or design of target specific oligonucleotides or binding molecules

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Plant Pathology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Bioinformatics & Computational Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • Immunology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Holo Graphy (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
  • Peptides Or Proteins (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

The invention describes a method for isolating one or more genetic elements encoding a gene product having a desired activity, comprising the steps of: (a) compartmentalising genetic elements into microcapsules; (b) expressing t he genetic elements to produce their respective gene products within the microcapsules; (c) sorting the genetic elements which produce the gene produ ct having the desired activity using a change in the optical properties of the genetic elements. The invention enables the in vitro evolution of nucleic acids and proteins by repeated mutagenesis and iterative applications of the method of the invention.

Claims (44)

1. A method for isolating one or more genetic elements encoding a gene product having a desired activity the expression of which may result, directly or indirectly, in the modification of an optical property of a genetic element encoding the gene product, comprising the steps of:
(a) compartmentalising genetic elements into microcapsules;
(b) expressing the genetic elements to produce their respective gene products within the microcapsules;
(c) sorting the genetic elements which produce the gene product(s) having the desired activity according to a change in the optical properties of the genetic elements.
2. A method according to claim 1, wherein in step (b) the activity of the desired gene product within the microcapsule results, directly or indirectly, in the modification of the genetic element encoding the gene product to enable the isolation of the genetic element.
3. A method according to claim 2, wherein in the modification of the genetic element within the microcapsule induces a change in its optical properties.
4. A method according to claim 2, wherein the modification of the genetic element enables it to be further modified outside the microcapsule so as to induce a change in its optical properties.
5. A method according to claim 2, wherein a part of the genetic element is a ligand and the desired gene product within the microcapsule binds, directly or indirectly, to said ligand to enable the isolation of the genetic element.
6. A method according to claim 5, wherein the ligand is also encoded by the genetic element.
7. A method according to claim 2, wherein a part of the genetic element is a substrate and the activity of the desired gene product within the microcapsule results, directly or indirectly, in the conversion of said substrate into a product which remains part of the genetic element and enables its isolation.
8. A method according to claim 2, wherein the product of the activity of the desired gene product within the microcapsule results, directly or indirectly, in the generation of a product which is subsequently complexed with the genetic element and enables its isolation.
9. A method according to any preceding claim wherein the activity of the desired gene product within the microcapsule results, directly or indirectly, in the alteration of the expression of a second gene within the compartment and the activity of the product of the said second gene enables the isolation of the genetic element using a change in the optical properties of the genetic element.
10. A method according to claim 1, wherein step (b) comprises:
expressing the genetic elements to produce their respective gene products within the microcapsules, linking the gene products to the genetic elements encoding them and isolating the complexes thereby formed.
11. A method according to claim 10, wherein in step (c) the complexes are directly sorted based on their changed optical properties to isolate genetic elements encoding a gene product having the desired activity.
12. A method according to claim 10, wherein in step (c) the complexes are further reacted to induce a conditional change in optical properties of the genetic element dependent on the presence of gene products with the desired activity in the complex.
13. A method according to claim 10, wherein the complexes are subjected to a further compartmentalisation step in order to isolate the genetic elements encoding a gene product having the desired activity.
14. A method according to claim 1, wherein the change in optical properties of the genetic element is due to binding of a gene product with distinctive optical properties to the genetic element.
15. A method according to claim 1, wherein the change in optical properties of the genetic element is due to binding of a ligand with distinctive optical properties by the gene product.
16. A method according to claim 1, wherein the change in optical properties of the genetic element is due to a change in the optical properties of the gene product when bound to ligand.
17. A method according to claim 1, wherein the change in optical properties of the genetic element is due to a change in the optical properties of the ligand when bound by the gene product.
18. A method according to claim 1, wherein the change in optical properties of the genetic element is due to a change in the optical properties of both ligand and gene product on binding.
19. A method according to claim 1, wherein the change in optical properties of the genetic element is due to the different optical properties of the substrate and the product of the reaction being selected.
20. A method according to claim 1, wherein both substrate and product have similar optical properties, but only the product, and not the substrate of the reaction being selected binds to, or reacts with, the genetic element, thereby changing the optical properties of the genetic element.
21. A method according to claim 1, wherein further reagents specifically bind to, or specifically react with. the product (and not the substrate) attached to the genetic element, thereby altering the optical properties of the genetic element.
22. A method according to any preceding claim, wherein a non-desired activity of a gene product results in a change in the optical properties of the genetic element which is distinct from that resulting from the desired activity.
23. A method according to claim 22, wherein the optical change resulting from the non-desired activity is used to negatively select the genetic elements.
24. A method according to claim 22, wherein negative selection is combined with positive selection to improve reaction specificity.
25. A method according to claim 24, wherein the improved reaction specificity is an improvement in binding specificity.
26. A method according to claim 24, wherein the improved reaction specificity is an improvement in regio- and/or stereo-selectivity for substrate and/or product.
27. A method according to any preceding claim, wherein the genetic elements are isolated from a library of genetic elements encoding a repertoire of gene products.
28. A method according to any preceding claim, wherein each genetic element encodes more two or more genes and each gene product must have a desired activity in order for the optical properties of the genetic element to be modified to enable them to be sorted.
29. A method according to any preceding claim, wherein each genetic element encodes two or more genes and the gene products must bind to each other in the microcapsule in order for the optical properties of the genetic element to be modified and the genetic elements sorted.
30. A method according to any preceding claim further comprising the additional step of:

(d) introducing one or more mutations into the genetic element(s) isolated in step (c).
31. A method according to any preceding claim further comprising iteratively repeating one or more of steps (a) to (d).
32. A method according to any preceding claim further comprising amplifying the genetic elements.
33. A method according to claim 1, wherein microencapsulation is achieved by forming a water-in-oil emulsion of the aqueous solution in an oil-based medium.
34. A method according to claim 1, wherein the genetic element comprises the gene attached to a microbead.
35. A method according to claim 1, wherein the microbead is nonmagnetic, magnetic or paramagnetic.
36. A method according to claim 1, wherein the genetic elements are sorted by detection of a change in their fluorescence.
37. A method according to claim 36, wherein the sorting of genetic elements is performed using a fluorescence activated cell sorter (FACS) (or similar device).
38. A method according to claim 36, wherein the different fluorescence properties of the substrate and the product are due to fluorescence resonance energy transfer (FRET).
39. A method according to any preceding claim, wherein the internal environment of the microcapsules is modified by the addition of one or more reagents to the oil phase.
40. A method according to any preceding claim, wherein genetic elements modified directly or indirectly by the activity of the desired gene product are further modified by Tyramide Signal Amplification (TSAT TM; NEN), resulting directly or indirectly in a change in the optical properties of said genetic elements thereby enabling their separation.
41. A product when isolated according to the method of any preceding claim.
42. A method for preparing a gene product, comprising the steps of:
(a) preparing a genetic element encoding the gene product;
(b) compartmentalising genetic elements into microcapsules;
(c) expressing the genetic elements to produce their respective gene products within the microcapsules;
(d) sorting the genetic elements which produce the gene product(s) having the desired activity using a change in their optical properties; and (e) expressing the gene product having the desired activity.
43. A method for screening a compound or compounds capable of modulating the activity of a gene product, comprising the steps of:
(a) preparing a repertoire of genetic elements encoding gene product;
(b) compartmentalising the genetic elements into microcapsules;
(c) expressing the genetic elements to produce their respective gene products within the microcapsules;
(d) sorting the genetic elements which produce the gene product(s) having the desired activity using a change in their optical properties; and (e) contacting a gene product having the desired activity with the compound or compounds and monitoring the modulation of an activity of the gene product by the compound or compounds.
44. A method for preparing a compound or compounds comprising the steps of:
(a) providing a synthesis protocol wherein at least one step is facilitated by a polypeptide;
(b) preparing genetic elements encoding variants of the polypeptide which facilitates this step;
(c) compartmentalising the genetic elements into microcapsules;
(d) expressing the genetic elements to produce their respective gene products within the microcapsules;

(e) sorting the genetic elements which produce polypeptide gene product(s) having the desired activity using a change in their optical properties; and (f) preparing the compound or compounds using the polypeptide gene product identified in (e) to facilitate the relevant step of the synthesis.
CA2357037A 1999-01-07 2000-01-06 Optical sorting method Expired - Lifetime CA2357037C (en)

Priority Applications (2)

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CA002584933A CA2584933A1 (en) 1999-01-07 2000-01-06 Optical sorting method
CA002479551A CA2479551A1 (en) 1999-01-07 2000-01-06 Optical sorting method

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9900298.2 1999-01-07
GBGB9900298.2A GB9900298D0 (en) 1999-01-07 1999-01-07 Optical sorting method
PCT/GB2000/000030 WO2000040712A1 (en) 1999-01-07 2000-01-06 Optical sorting method

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CA2357037C CA2357037C (en) 2012-12-11

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US (6) US6808882B2 (en)
EP (4) EP1905828B1 (en)
JP (5) JP4851008B2 (en)
AT (3) ATE366307T1 (en)
AU (1) AU781217B2 (en)
CA (3) CA2479551A1 (en)
DE (2) DE60043289D1 (en)
DK (2) DK1522581T3 (en)
ES (4) ES2333844T3 (en)
GB (1) GB9900298D0 (en)
WO (1) WO2000040712A1 (en)

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